PROJECT SUMMARY/ABSTRACT This application is being submitted in response to RFA DK-17-509 which solicits applications from qualified investigators for the continuation of the Drug Induced Liver Injury Network (DILIN). Indiana University is one of the five founding clinical centers and has robustly participated in all DILIN operations since its inception. We propose the following specific aims to meet the goals of this RFA. Specific Aim # 1: To enroll large number of eligible adults and children with suspected DILI into ongoing DILIN studies. We propose to collect acute, prospective and retrospective cases of suspected DILI from multiple sources in Central Indiana, each providing distinctive epidemiological facets and research potential. A special focus of this aim is to robustly enroll two subpopulations: (a) individuals with suspected liver injury due to chemo-and immunotherapeutic agents; and (b) individuals with severe skin adverse reactions who also exhibit liver injury. Specific Aim # 2: To conduct three distinct ancillary studies, each one adding significantly to our understanding of DILI. These include: (a) to develop and validate a model consisting of severity of liver injury and co-morbidities to predict six-month mortality in individuals presenting with DILI; (b) to systematically search for medications as triggers for new- onset autoimmune hepatitis; and (c) to investigate HLA variants associated with DILI with immunoallergic features including skin reactions. Specific Aim # 3: DILI carries considerable mortality and morbidity but there is no treatment available other than withdrawing the offending agent. In order to address this unmet therapeutic need, we propose to conduct a randomized, double-blind, placebo-controlled pilot study of budesonide in individuals with well characterized hepatocellular DILI meeting predefined eligibility criteria. Our hypothesis is that oral budesonide, a steroid with high glucocorticoid activity and substantial first pass elimination, attenuates liver injury and improves outcomes of patients with hepatocellular DILI. Fifty individuals with definite, highly likely or probably DILI with hepatocellular DILI (R>5) and total bilirubin > 5 mg/dL will be randomized to receive either budesonide (9 mg once daily) or placebo for 4 weeks. Primary efficacy endpoint is proportion of patients with improvement in total bilirubin from peak to 2.5 mg/dL at 4 weeks. Primary safety endpoint is the proportion of patients with serious adverse events in each group. Specific Aim # 4: The objective is to robustly participate in the cross-consortia activities including participating and leading (where appropriate) steering committee, genetics committee, ancillary studies committee, publications and presentations committee, causality committee, and herbal and dietary supplements (HDS) committee activities.